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Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease.
Stadler, Karina A; Ortiz-Joya, Lesly J; Singh Sahrawat, Amit; Buhlheller, Christoph; Gruber, Karl; Pavkov-Keller, Tea; O'Hagan, Treasa B; Guarné, Alba; Pulido, Sergio; Marín-Villa, Marcel; Zangger, Klaus; Gubensäk, Nina.
Afiliación
  • Stadler KA; Institute of Chemistry/Organic and Bioorganic Chemistry, University of Graz, Graz, Austria.
  • Ortiz-Joya LJ; Institute of Chemistry/Organic and Bioorganic Chemistry, University of Graz, Graz, Austria.
  • Singh Sahrawat A; Programa de Estudio y Control de Enfermedades Tropicales (PECET), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
  • Buhlheller C; Department of Biochemistry, McGill University, Montreal, Canada.
  • Gruber K; Institute of Molecular Biosciences, University of Graz, Graz, Austria.
  • Pavkov-Keller T; Innophore GmbH, Graz, Austria.
  • O'Hagan TB; Institute of Molecular Biosciences, University of Graz, Graz, Austria.
  • Guarné A; Institute of Molecular Biosciences, University of Graz, Graz, Austria.
  • Pulido S; Innophore GmbH, Graz, Austria.
  • Marín-Villa M; Field of Excellence BioHealth, University of Graz, Graz, Austria.
  • Zangger K; BioTechMed-Graz, Graz, Austria.
  • Gubensäk N; Institute of Molecular Biosciences, University of Graz, Graz, Austria.
Sci Rep ; 14(1): 10039, 2024 05 02.
Article en En | MEDLINE | ID: mdl-38693166
ABSTRACT
According to the World Health Organization, Chagas disease (CD) is the most prevalent poverty-promoting neglected tropical disease. Alarmingly, climate change is accelerating the geographical spreading of CD causative parasite, Trypanosoma cruzi, which additionally increases infection rates. Still, CD treatment remains challenging due to a lack of safe and efficient drugs. In this work, we analyze the viability of T. cruzi Akt-like kinase (TcAkt) as drug target against CD including primary structural and functional information about a parasitic Akt protein. Nuclear Magnetic Resonance derived information in combination with Molecular Dynamics simulations offer detailed insights into structural properties of the pleckstrin homology (PH) domain of TcAkt and its binding to phosphatidylinositol phosphate ligands (PIP). Experimental data combined with Alpha Fold proposes a model for the mechanism of action of TcAkt involving a PIP-induced disruption of the intramolecular interface between the kinase and the PH domain resulting in an open conformation enabling TcAkt kinase activity. Further docking experiments reveal that TcAkt is recognized by human inhibitors PIT-1 and capivasertib, and TcAkt inhibition by UBMC-4 and UBMC-6 is achieved via binding to TcAkt kinase domain. Our in-depth structural analysis of TcAkt reveals potential sites for drug development against CD, located at activity essential regions.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trypanosoma cruzi / Enfermedad de Chagas / Simulación de Dinámica Molecular / Simulación del Acoplamiento Molecular Límite: Humans Idioma: En Revista: Sci Rep Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trypanosoma cruzi / Enfermedad de Chagas / Simulación de Dinámica Molecular / Simulación del Acoplamiento Molecular Límite: Humans Idioma: En Revista: Sci Rep Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Reino Unido